Circadian desynchrony is a phenomenon that occurs when the internal circadian clock is misaligned with the social schedule that one tries to keep. This arises volitionally in a variety of circumstances, including shift work and jet travel. It leads to significant pathophysiology including deleterious changes in sleep, cognition, metabolism, immune function, and cardiac function, which in turn can lead to, among other things, increases in obesity, cancer risk, and workplace accidents. Circadian desynchrony also occurs naturally in delayed sleep phase disorder (DSPD), a condition in many adolescents and young adults that is compounded by social pressures and causes individuals to shift their sleep time later while their wake time remains fixed. DSPD leads to significant decline in workplace and academic performance and has been linked to a variety of disorders including obesity and depression. Circadian desynchrony is most readily treated by hours of administration of bright light. This, however, is not always possible and our lack of complete understanding of the characteristics of light and how it influences the circadian pacemaker limit our ability to design better countermeasures to circadian desynchrony. It is the purpose of this application to examine the basic physiology of how light influences circadian timing, as well as how light impacts alertness at night and a novel mechanism by which to change circadian timing during sleep. Specifically, we will examine the hypothesis that when subjects are exposed, while awake at night, to ultrashort (millisecond) pulses of light, the light is able to both synchronize the human circadian system and improve alertness, as determined by both subjective and objective measures. In a separate experiment, subjects will be exposed to ultrashort pulses of light at night while they sleep. In that experiment, we intend to examine the hypothesis that this stimulus will not only penetrate the closed eyelid and synchronize the circadian system, but that it will do so without disrupting sleep. In order to examine these hypotheses, young, healthy subjects will be brought into a specially designed human circadian laboratory and exposed to different regimens of light. We introduce in this study a novel protocol that reduces the study length of stay from the standard week to just two days. While greatly reducing subject burden and study costs, we are able to maintain high fidelity measurements of the human circadian system. We will also examine alertness through a variety of techniques including performance tracking and examination of electroencephalographic activity. Results from this experiment will not only fundamentally change the manner in which we think about how light affects the human circadian pacemaker, but it will also lead to direct, testable therapeutics for the treatment of circadian desynchrony. It may also lead to a better understanding of the impact of light on other hypothalamic- influenced functions including mood and endocrine function. PUBLIC HEALTH RELEVANCE: The lack of synchrony between the internal circadian clock and the outside world is increasingly becoming a significant problem in our round-the-clock lives and leads to significant negative health consequences, including an increased cancer risk, workplace accidents, and obesity. In fact, the International Agency for Research on Cancer, the cancer arm of the World Health Organization, classifies shift work as a probable carcinogen. This project intends to examine the brain physiology underlying the synchronization of the internal circadian clock to the external world and will test a novel method of synchronizing this brain clock, one that could lead to a novel therapy for shift workers, jet travelers, and adolescents with delayed sleep phase syndrome.